Sequence specific antimicrobials
AssigneeThe Rockefeller University
InventorsDavid Bikard, Luciano Marraffini
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Abstract
Provided are compositions and methods for selectively reducing the amount of antibiotic resistant and/or virulent bacteria in a mixed bacteria population, or for reducing any other type of unwanted bacteria in a mixed bacteria population. The compositions and methods involve targeting bacteria that are differentiated from other members of the population by at least one unique clustered regularly interspaced short palindromic repeats (CRISPR) targeted DNA sequence. The compositions and methods can be readily adapted to target any bacteria or any bacteria plasmid, or both.
Claims20
A pharmaceutical composition for selectively reducing the amount of antibiotic resistant and/or virulent Staphylococcus aureus (S. aureus) bacteria in a mixed bacterial population, the composition comprising a pharmaceutically acceptable carrier and a packaged, recombinant phagemid, wherein the phagemid comprises a clustered regularly interspaced short palindromic repeats (CRISPR) system, wherein the CRISPR system comprises nucleotide sequences encoding:
- i) a CRISPR-associated (Cas) 9 enzyme;
- and
- ii) a targeting RNA selected from:
- a) at least one S. aureus chromosome targeting RNA;
- b) at least one S. aureus plasmid targeting RNA;
- and
- c) a combination of a) and b).
The pharmaceutical composition of claim 6, wherein the antibiotic resistance gene is a methicillin resistance gene.
A method for reducing the amount of virulent and/or antibiotic resistant Staphylococcus aureus (S. aureus) in a bacterial population, the method comprising:
- contacting the bacterial population with a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a packaged, recombinant phagemid, wherein the phagemid comprises a clustered regularly interspaced short palindromic repeats (CRISPR) system, wherein the CRISPR system comprises nucleotide sequences encoding:
- i) a CRISPR-associated (Cas) 9 enzyme;
- and
- ii) a targeting RNA selected from:
- a) at least one S. aureus chromosome targeting RNA,
- b) at least one S. aureus plasmid targeting RNA;
- and
- c) a combination of a) and b);
- wherein the contacting the bacterial population is such that at least some of the phagemids are introduced into at least some of the bacteria in the bacterial population and, subsequent to the introduction of the phagemids, at least the targeting RNA and the Cas9 enzyme are produced, and wherein the amount of the virulent and/or antibiotic resistant S. aureus in the mixed bacterial population is reduced.
A method for personalized therapy for an individual in need of therapy for a bacterial infection comprising:
- i) obtaining a biological sample from the individual and determining a plurality of bacterial DNA sequences from the sample;
- ii) based on the determining of the sequences, identifying one or more pathogenic bacterial species that were in the sample;
- and
- iii) administering to the individual a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a packaged, recombinant phagemid, wherein the phagemid comprises a clustered regularly interspaced short palindromic repeats (CRISPR) system, wherein the CRISPR system comprises nucleotide sequences encoding:
- i) a CRISPR-associated (Cas) 9 enzyme;
- and
- ii) a targeting RNA selected from:
- a) a targeting RNA targeted to a chromosome of the identified pathogenic bacteria;
- or
- b) a targeting RNA targeted to a plasmid of the identified pathogenic bacteria;
- or
- c) a combination of a) and b);
- wherein the administering is such that at least some of the phagemids are introduced into at least some of the pathogenic bacteria in or on the individual and, subsequent to the introduction of the phagemids, at least the targeting RNA and the Cas9 enzyme are produced, and wherein the amount of pathogenic bacteria and/or the amount of the plasmids is reduced.
Dependencies are inferred from the claim text.